Identification and validation of a novel prognostic index based on m6A RNA methylation regulators in esophageal carcinoma

Abstract

Background The incidence and mortality rate of esophageal carcinoma (ESCA) remains high. This study proposed to explore the promising prognostic markers based on m6A RNA methylation regulators, and finally to improve the prognostic assessment for ESCA patients. Methods The RNA sequencing and relevant clinical data of ESCA and normal tissues were obtained from The Cancer Genome Atlas (TCGA) database. Then, we evaluated the expression pattern of 13 m6A methylation regulators in ESCA and normal samples. Two groups of ESCA were divided by the consensus clustering analysis. STRING database and R package were used to construct the protein-protein interaction network and conduct correlation analysis, respectively. Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed to develop the multiple-gene risk signature. Kaplan-Meier method and receiver operating characteristic (ROC) curves were used to assess the accuracy of the model. The clinical nomogram combining clinicpathological factors and gene signature was built to predict survival rate of ESCA patients. Gene set enrichment analysis (GSEA) and networks prediction analysis were conducted to explore the signaling pathways that related to the risk genes. Results Eight m6A methylation regulators (HNRNPC, YTHDF1, METTL3, YTHDF2, WTAP, YTHDC1, KIAA1429, and RBM15) were significantly upregulated in ESCA. Two clusters of ESCA with obvious differences in tumor stage were identified via the consensus clustering analysis. A two-gene signature, ALKBH5 and HNRNPC, was established for predicting the prognosis of ESCA patients. Kaplan-Meier curves illustrated that the overall survival of patients in low-risk group was obviously longer than that of patients in high-risk group (P = 1.411e-02). Importantly, risk score and tumor stage were identified as the independent prognostic indicators. The testing dataset GSE13898 showed that the nomogram had a good capacity to assess the prognosis of ESCA patients. Cell cycle, mTOR pathway, and p53 signaling pathway were found to be related to the dysregulation of risk genes. Conclusions m6A RNA methylation regulators ALKBH5 and HNRNPC could act as prognostic indicators and therapeutic targets for prognostic analysis and cancer treatment of ESCA.

The m6A RNA methylation regulates oncogenic signaling pathways driving cell malignant transformation and carcinogenesis

“…In an effort to identify and validate the prognostic signature of the m 6 A regulators in esophageal carcinoma (ESCA), Yang and colleagues observed several m 6 A regulatory proteins that were upregulated in ESCA. Among these, high expression phenotype of HNRNPC was associated with activation of cell cycle and p53 signaling pathway [59]. Low expression of m 6 A eraser ALKBH5 was found in a cohort of pancreatic cancer (PC) patients in which both the mRNA and protein levels of ALKBH5 were downregulated in the cancerous tissues compared to the noncancerous pancreatic tissues.…”